Indoline compounds for synthesis of pharmaceutically active pyrrolobenzimidazoles

ABSTRACT

The present invention provides Indolines of the formula: ##STR1## ps useful to provide pharmaceutically active pyrrolobenzimidazoles or tautomers thereof, of the formula:   These compounds are useful for treating heart or circulatory diseases, especially those which respond to a change of blood pressure, an increase in cardiac output and/or a change in micro-circulation.

This application is a continuation-in-part of U.S. application Ser. No.820,259 now U.S. Pat. No. 4,695,567.

The present invention is concerned with new indoline intermediates forthe preparation of pharmaceutically active pyrrolobenzimidazoles,processes for the preparation thereof and pharmaceutical compositionsfor said pyrrolobenzimidazoles.

The pyrrolobenzimidazoles according to the present invention arecompounds of the general formula: ##STR2## and the new indolines of theinvention are compounds of the general formula II and III: ##STR3##wherein R₁ is a hydrogen atom or an alkyl, alkenyl or cycloalkylradical, R₂ is a hydrogen atom, an alkyl or alkenyl radical, a cyanogroup, a carbonyl group substituted by a hydroxyl, alkyl, alkoxy, amino,alkylamino, dialkylamino or hydrazino group or, together with R₁,represents a cycloalkylene radical or R₁ and R₂ together form analkylidene or cycloalkylidene radical, X is a valency bond, a C₁ -C₄alkylene radical or a vinylene radical, T is an oxygen or sulphur atomand Het is a heterocyclic six-membered ring with an oxygen or sulphuratom, a heterocyclic five-membered ring with 1 to 4 heteroatoms or aheterocyclic six-membered ring with 2 to 5 heteroatoms, whereby thehetero atoms of the said five- or six-membered rings can be the same ordifferent and are nitrogen, oxygen or sulphur atoms and can optionallycarry an oxygen atom on one or more nitrogen atoms and the said five-and six-membered rings can optionally be substituted by one or morealkyl, alkoxy, alkylthio, hydroxyl, oxo, nitro, amino, halogeno,carboxyl, alkoxycarbonyl, aminocarbonyl or cyano groups; their tautomersand their physiologically acceptable salts with inorganic and organicacids.

Since the compounds of general formula (I), when R₁ is not the same asR₂, possess an asymmetric carbon atom, the present invention alsoincludes the optically-active forms and the racemic mixtures of thesecompounds.

The new compounds according to the present invention possess valuablepharmacological properties and, in particular, they increase thestrength of the heart and/or have a blood pressure-lowering actionand/or influence the thrombocyte function and improve themicrocirculation.

In general formula (I), the substituents R₁ and/or R₂ preferablyrepresent hydrogen atoms, straight-chained or branched alkyl or alkyleneradicals containing 1 to 6 and 2 to 6 carbon atoms, respectively,cycloalkyl radicals containing 3 to 7 carbon atoms, cyano groups orcarboxyl groups substituted by a hydroxyl, alkyl, alkoxy, amino,alkylamino, dialkylamino or hydrazino group, wherein the alkyl moietycontains up to 6 and preferably up to 3 carbon atoms. More particularly,R₁ and/or R₂ can represent atoms, methyl, ethyl, isopropyl, 3-pentyl,cyclopentyl, cyclohexyl, allyl, cyano, acetyl, propionyl,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl or hydrazinocarbonyl groups.

R₁ and R₂ can, together with the carbon atom to which they are attached,also form a cycloalkyl ring containing 3 to 8 carbon atoms andpreferably a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl orspirocyclohexyl radical.

R₁ and R₂ can together also form an alkylidene or cycloalkylideneradical and preferably an isopropylidene radical.

X is a valency bond, a C₁ -C₄ alkylene radical or a vinylene radical butpreferably a valency bond or a methylene or vinylene radical.

T is an oxygen or sulphur atom but preferably an oxygen atom.

If Het signifies a heterocyclic six-membered ring with one oxygen or onesulphur atom, a heterocyclic five-membered ring with 1 to 4 heteroatomsor a heterocyclic six-membered ring with 2 to 5 heteroatoms, wherein theheteroatoms of the said five- and six-membered rings can be the same ordifferent and signify nitrogen, oxygen or sulphur and can possibly carryan oxygen atom on one or more nitrogen atoms, then they are preferablypyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl,oxazoyl, pyronyl, 2-methyloxazolyl, 5-methyloxazolyl,2-methylpyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl,pyrazinyl, N-,N-dioxypyrazinyl, pyrimidinyl, N,N-dioxypyrimidinyl,pyrimidinonyl, pyridazinyl, oxazinyl, thiazinyl, triazinyl, ortetrazinyl or the above substituted rings.

Alkyl, alkoxy and alkylthio substituents in the heterocyclic five- andsix-membered rings can contain up to 6 and preferably up to 4 carbonatoms, the methyl, ethyl, methoxy, ethoxy, methylthio and ethylthioradicals being preferred specially preferred substituted heterocyclicfive- and six-membered rings are for example 2-methyl oxazole,5-methypyrazole, 2-methylpyrimidine and 6-hydroxy-pyridizine.

Halogen is to be understood to mean fluorine, chlorine or bromine,chlorine being preferred.

Preferred substituents of the heterocyclic five- and six-membered ringsinclude oxo, hydroxyl, methyl, methoxy, methylthio, carboxyl,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, amino, nitro, halogenoor cyano groups and especially hydroxyl, methyl, methylthio, carboxyl,methoxycarbonyl, aminocarbonyl and cyano groups. The oxo-substitutedheterocyclic five- or six-membered rings can carry an oxygen atom on thecarbon atom of the ring and can be for example pyrone or pyrimidinone.

The compounds of general formula (I) can be prepared according to thefollowing reaction schemes 1 and 2.

As can be seen from scheme 1, compounds of general formulae (II) and(III) are converted by nitration or by acylation of theaminonitroindolinones (IV) and (V) with compounds of general formula(IX) into compounds of general formulae (VI) and (VII), wherein R₁, R₂,Het and X have the same meanings as above. From compounds of generalformulae (VI) and (VIII), by reduction of the nitro group, or fromcompounds of general formula (VIII) by reaction with compounds ofgeneral formula (IX), there are obtained compounds of general formula(I) or tautomers thereof, wherein R₁, R₂, Het and X have the samemeanings as above. ##STR4##

In general formula (IX), Het and X have the above-given meanings and Yis either a hydrogen atom or a residue which can easily be split off. Inparticular, compounds of general formula (IX) are to be understood to bealdehydes, as well as acid halides, such as acid chlorides, carboxylicacid esters, for example methyl and ethyl esters, and other activatedcarboxylic acid derivatives, for example anhydrides.

If the compound of general formula (IX) is an aldehyde, the reaction tothe Schiff base with compounds of general formula (VIII) preferablytakes place in an alcoholic medium, the subsequent cyclisation andoxidation to give compounds of general formula (I) taking place byheating the reaction mixture under reflux in the presence of atmosphericoxygen and catalytic amounts of an acid, for example toluenesulphonicacid.

If the compound of general formula (IX) is a carboxylic acid derivative,the reaction with a compound of general formulae (VI), (VII) and (VIII)to give an amide suitably takes place in an inert solvent, preferably inmethylene chloride or pyridine, and the subsequent cyclisation to givecompounds of general formula (I) is, after previous hydrogenation of thenitro group in compounds of general formulae (VI) and (VII), carried outin a solvent or solvent mixture, for example ethanol, isopropanol,glacial acetic acid, benzene, chlorobenzene, glycol, diethylene glycoldimethyl ether, sulfolan or diemthylformamide, at a temperature of from0° to 250° C. but preferably at the boiling point of the reactionmixture, optionally in the presence of a condensation agent, for examplephosphorus oxychloride, thionyl chloride, p-toluenesulphonic acid,hydrochloric acid, sulphuric acid, phosphoric acid or polyphosphoricacid, or possibly in the presence of a base, for example sodiumhydroxide, potassium methylate or potassium tert.-butylate. However, thecyclisation can also be carried out without the use of a solvent and/orof a condensation agent.

The above-mentioned hydrogenation of the nitro group is preferablycarried out in a solvent, for example water, ethanol, glacial aceticacid, ethyl acetate or dimethylformamide, preferably with hydrogen inthe presence of a hydrogenation catalyst, for example Raney nickel,platinum or palladium/charcoal, or with a metal, for example, iron, tinor zinc, in the presence of an acid, or with a salt, for example ferroussulphate, stannous chloride, sodium sulphide, sodium hydrogen sulphideor sodium dithionite, or with hydrazine in the presence of Raney nickel,at a temperature of from 0° to 250° C. but preferably at ambienttemperature.

The compounds of general formulae (IV), (V) and (VIII) are known fromthe literature (cf. Federal Republic of Germany Patent Application No. P34 17 643.8). Compounds of general formula (VI) and (VII) are new andare also the subject of the present invention.

As can be seen from scheme 2, the compounds of general formula (I) andthe tautomeric forms thereof can also be prepared by various processesknown from the literature from compounds of general formula (X), whereinHet and X have the above-given meanings (cf. in this regard, R. C.Elderfield (ed.); P. L. Julian, E. W. Meyer and H. C. Printy,Heterocyclic Compounds, Vol. 3, 126-142, pub. John Wiley & Sons, 1952,New York).

Hinsberg synthesis: reaction of aromatic amines with the bisulphiteaddition compounds of ketones

Brunner synthesis: cyclisation of aromatic amines via the hydrazite tooxindoles.

Stolle synthesis: cyclisation of aromatic amines via an amide to theoxindole. ##STR5##

Some of the compounds of general formula (X) are new and can be preparedby processes known from the literature.

Compounds of general formula (I) can also be subsequently converted intoother compounds of general formula (I). This applies, for example:

(a) For the oxidation of a five- or six-membered ring with one or morenitrogen atoms to give the corresponding N-oxides, the oxidation ispreferably carried out with one or more equivalents of the oxidationagent employed, for example with hydrogen peroxide in glacial aceticacid, trifluoroacetic acid or formic acid at 20° to 100° C. or inacetone at 0° to 60° C.; with a per acid, for example performic acid orm-chloroperbenzoic acid, in glacial acetic acid, trifluoroacetic acid,methylene chloride or chloroform, at a temperature of from 0° to 60° C.

(b) For the hydrogenation of a vinylene compound (X=--CH═CH--) into thecorresponding ethylene compound (X=--CH₂ --CH₂ --), the hydrogenation ispreferably carried out in a solvent, for example water, water/ethanol,methanol, glacial acetic acid, ethyl acetate or dimethylformamide,preferably with hydrogen in the presence of a hydrogenation catalyst,for example Raney nickel, platinum or palladium/charcoal.

(c) For the reaction of a compound of general formula (I), wherein R₁and R₂ are hydrogen atoms, with a compound of the general formula:##STR6## wherein R₃ and R₄ are alkyl radicals or R₃ together with R₄forms a C₃ -C₇ -cycloalkylene radical, to give a compound of generalformula (I), wherein R₁ together with R₂ represents an alkylidene orcycloalkylidene radical, as well as the optional hydrogenation thereofto give corresponding compounds of general formula (I), wherein R₁ andR₂ are hydrogen atoms.

The reaction with compounds of general formula (XI) is preferablycarried out in a polar solvent, for example ethanol ordimethylformamide, in the presence of a base, for example ammonia ortriethylamine, or also in the presence of an acid, for examplehydrochloric acid, sulphuric acid, phosphoric acid, polyphosphoric acidor p-toluenesulphonic acid, at 20° to 250° C. but preferably at theboiling temperature of the solvent.

The hydrogenation which is optionally to be carried out is carried outunder the conditions described above under (b).

(d) For the reaction of compounds of general formula (I), wherein R₁ orR₂ is a carboxyl group or a reactive derivative thereof, for example anester or acid chloride, with hydrazine or with an amine of the generalformula:

    R.sub.5 --NH--R.sub.6                                      (XII)

wherein R₅ and R₆, which can be the same or different, are hydrogenatoms or alkyl radicals containing up to 5 carbon atoms, or with areactive derivative thereof, if R₁ or R₂ is a carboxyl group, to givecompounds of general formula (I), wherein R₂ is a carboxyl groupsubstituted by an amino, alkylamino, dialkylamino or hydrazino group.

The reaction is preferably carried out in a solvent or solvent mixture,for example methylene chloride, ethanol, chloroform, carbontetrachloride, diethyl ether, tetrahydrofuran, dioxan, benzene,acetonitrile or dimethylformamide, optionally in the presence of anagent activating the acid or of a water-removing agent, for example inthe presence of ethyl chloroformate, thionyl chloride, phosphorustrichloride, phosphorus pentoxide, N',N-dicyclohexyl carbodiimide,N',N-dicyclohexyl carbodiimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole or N,N'-thionyl diimidazole or of triphenylphosphine/carbon tetrachloride, or of an agent activating the hydrazinoor amino group, for example phosphorus trichloride, and optionally inthe presence of an inorganic base, for example sodium carbonate, or of atertiary organic base, for example triethylamine or pyridine; which cansimultaneously serve as a solvent, at a temperature of from -25° to 250°C. but preferably at a temperature of from -10° C. and the boilingtemperature of the solvent used. Furthermore, water formed during thereaction can be separated off by azeotropic distillation, for example byheating with toluene on a water separator, or by the addition of adrying agent, for example anhydrous magnesium sulphate or a molecularsieve.

However, the reaction is carried out especially advantageously in acorresponding halide, for example the carboxylic acid chloride, andhydrazine or a corresponding amine, whereby these can simultaneouslyserve as solvent, at a temperature of from 0° to 50° C.

(e) For the reaction of a compound of general formula (I), wherein R₁ orR₂ represents an aminocarbonyl group, to give a compound of generalformula (I), wherein R₁ or R₂ is a cyano group, the reaction ispreferably carried out in an inert solvent, for example methylenechloride, chloroform, dioxan, pyridine, xylene or chlorobenzene, in thepresence of a water-removing agent, for example thionyl chloride,phosphorus trichloride, phosphorus pentoxide, phosphorus pentachloride,aluminium chloride, benzenesulphonic acid chloride, toluenesulphonicacid chloride, triphenyl phosphine, boron trifluoride or ethylpolyphosphate, at a temperature of from 50° to 250° C. but preferably atthe boiling temperature of the solvent.

(f) For the reaction of a compound of general formula (I), wherein R₁ orR₂ is a cyano group, to give another compound of general formula (I),wherein R₁ or R₂ form a carboxyl, aminocarbonyl or alkoxycarbonyl with atotal of up to 6 carbon atoms, alcoholysis and/or hydrolysis ispreferably carried out in the presence of an acid, for examplehydrochloric acid, sulphuric acid, phosphoric acid or trichloroaceticacid, or in the presence of a base, for example sodium hydroxide orpotassium hydroxide, in an appropriate solvent, for example water,water/methanol, ethanol, water/isopropanol or water/dioxan, at atemperature of from -10° to 120° C., for example at a temperature offrom ambient temperature to the boiling temperature of the reactionmixture.

(g) For the reaction of a compound of general formula (I), wherein T isan oxygen atom, to give another compound of general formula (I), whereinT is a sulphur atom, the reaction is carried out by processes known fromthe literature with a reagent transferring the sulphur atom, for examplephosphorus pentasulphide, whereby 1 to 5 mole but preferably 1 mole ofphosphorus pentasulphide is used in an appropriate solvent. As solvent,there can be used, for example, tetrahydrofuran, dioxan, benzene,toluene or pyridine, at a temperature of from 25° to 125° C. However, itis preferred to use pyridine with a reaction time of from 1 to 10 hoursand preferably of 5 hours, depending upon the nature of the reactioncomponents.

Furthermore, the compounds obtained of general formula (I) can, ifdesired, be subsequently converted into their physiologically acceptableacid-addition salts with inorganic and organic acids. As acids for thispurpose, there can be used, for example, hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,tartaric acid, citric acid, lactic acid, maleic acid andmethanesulphonic acid.

For the preparation of pharmaceutical compositions, the compounds ofgeneral formula (I) can be mixed in known manner with appropriatepharmaceutical carrier substances, aroma, flavouring and colouringmaterials and formed, for example, into tablets or dragees or, with theaddition of appropriate adjuvants, can be suspended or dissolved inwater or an oil, for example olive oil.

The new compounds of general formula (I) according to the presentinvention and the salts thereof can be administered enterally orparenterally in liquid or solid form. As injection medium, it ispreferred to use water which contains the additives usual for injectionsolutions, for example stabilising agents, solubilising agents orbuffers.

Additives of this kind include, for example, tartrate and citratebuffers, ethanol, complex formers (such as ethylenediamine-tetraaceticacid and the nontoxic salts thereof) and high molecular weight polymers(such as liquid polyethylene oxide) for viscosity regulation. Solidcarrier materials include, for example, starch, lactose, mannitol,methyl cellulose, talc, highly dispersed silicic acids, high molecularweight fatty acids (such as stearic acid), gelatine, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats and solid highmolecular weight polymers (such as polyethylene glycols). Compositionssuitable for oral administration can, if desired, contain flavouring andsweetening agents.

The compounds according to the present invention are usuallyadministered in amounts of from 10 to 500 mg. per day, referred to abody weight of 75 kg. It is preferred to administer, 2 to 3 times a day,1 to 2 tablets with an active material content of 5 to 200 mg. Thetablets can also be retarded, in which case 1 to 2 tablets containing 10to 500 mg. of active material are to be given once per day. The activematerial can also be administered by injection 1 to 8 times per day orby continuous infusion, in which case amounts of from 5 to 200 mg./daynormally suffice.

As already mentioned, compounds of general formulae (VI) and (VII) arealso new and are the subject of the present invention.

Apart from the compounds mentioned in the following Examples, compoundsof general formulae (VI) and (VII) according to the present inventionalso include the following compounds:

6-nitro-5-(2-furanylcarbonylamino)-indolin-2-one

6-nitro-5-(3-pyridazinylcarbonylamino)-3,3-dimethylindolin-2-one

6-nitro-5-[(6-methylpyrimidin-4-yl)-carbonylamino]-3,3-dimethylindolin-2-one

6-nitro-5-[(1,2,5-thiadiazol-3-yl)-carbonylamino]-3,3-dimethylindolin-2-one

6-nitro-5-[(1,3,4-thiadiazol-2-yl)-carbonylamino]-3,3-dimethylindolin-2-one

6-nitro-5-(2-furanylcarbonylamino)-3,3-diethylindolin-2-one

6-nitro-5-(4-pyridazinylcarbonylamino)-3-isopropylideneindolin-2-one

5-nitro-6-[(2-hydroxypyrimidin-5-yl)-carbonylamino]-3-methylindolin-2-one

5-nitro-6-[(3,6-dimethylpyridazin-4-yl)-carbonylamino]-3-methylindolin-2-one

5-nitro-6-[(1-methyl-2-oxopyrimidin-5-yl)-carbonylamino]-3-ethylindolin-2-one

5-nitro-6-[(1,2,5-oxadiazol-3-yl)-carbonylamino]-3-cyclopentylindolin-2-one

5-nitro-6-(3-pyridazinylcarbonylamino)-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-(4-pyrimidinylcarbonylamino)-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-(2-pyrazinylcarbonylamino)-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(2-methylpyrimidin-5-yl)-carbonylamino]-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(1-methyl-2-oxopyrimidin-5-yl)-carbonylamino]-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(6-methylpyrimidin-4-yl)-carbonylamino]-3-methyl-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(6-hydroxypyridazin-3-yl)-carbonylamino]-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(3,6-dimethylpyridazin-4-yl)-carbonylamino]-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(1,3,5-thiadiazol-2-yl)-carbonylamino]-3-ethoxycarbonylindolin-2-one

5-nitro-6-[(2-methylpyrimidin-5-yl)-carbonylamino]-3-methyl-3-acetylindolin-2-one.

New compounds of general formula (I) include, apart from the compoundsmentioned in the Examples, also the following:

7,7-dimethyl-2-(3-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(6-methylpyrimidin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(3-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(2-thienylmethyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(2,6-dihydroxypyrimidin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-oxazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(1,3,4-thiadiazol-2-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(1,2,3-thiadiazol-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one;m.p. >300° C., recrystallised from isopropanol

7,7-dimethyl-2-(1,2,3-thiadiazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(2-methylthio-1,3,4-oxadiazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-carboxy-1,2,3-1H-triazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-methoxycarbonyl-1,2,3-1H-triazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-aminocarbonyl-1,2,3-1H-triazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(4-cyano-1,2,3-1H-triazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-dimethyl-2-(5,6-dimethyl-1,2,4-triazin-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7,7-diethyl-2-(2-furanyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

2'-(2-furanyl)-spiro[cyclopentan-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'-f]benzimidazol]-6'-one;m.p. >300° C., recrystallized from methyl ethyl ketone

2'-(4-pyridazinyl)-spiro[cyclopentan-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'-f]benzimidazol]-6'-one

7-methyl-2-(2-pyrrolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(2-hydroxypyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(3,6-dimethylpyridazin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(2-oxopyran-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(2,6-dihydroxypyrimidin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(2-oxazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-2-(1,3,5-triazin-2-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(4-imidazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(1-methyl-2-oxopyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(2-imidazolyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(3-methyl-1,2,4-triazin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(2-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(1,2,4-triazin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethyl-2-(4-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-isopropyl-2-(4-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-isopropyl-2-(1,2,4,5-tetrazin-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-cyclopentyl-2-(5-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-cyclopentyl-2-(1,2,5-oxadiazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-isopropylidene-2-(4-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-isopropylidene-2-(1H-tetrazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

2-(2-furanyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(3-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(4-pyrimidinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(2-pyrazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(2-hydroxypyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(1-methyl-2-oxopyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(6-methylpyrimidin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(5-oxazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(2-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(4-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(1,2,4-triazin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-ethoxycarbonyl-2-(5-methylpyrazol-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]-benzimidazol-6-one

7-methyl-7-aminocarbonyl-2-(4-pyrimidinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-aminocarbonyl-2-(5-oxazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-methylaminocarbonyl-2-(1-methyl-2-oxopyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-methylaminocarbonyl-2-(1,3,4-triazin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-dimethylaminocarbonyl-2-(6-methylpyrimidin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-dimethylaminocarbonyl-2-(5-methylpyrazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-cyano-2-(2-pyrazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-cyano-2-(2-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-hydrazinocarbonyl-2-(2-methylpyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-hydrazinocarbonyl-2-(4-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-acetyl-2-(2-hydroxypyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methyl-7-acetyl-2-(1,3,5-triazin-2-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(6-hydroxypyridazin-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(3,6-dimethylpyridazin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(1,2,4-triazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(3-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(1,2,5-thiadiazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(2-oxopyran-5-yl)-6,7-dihydro-3H,5H-pyrrollo[2,3-f]benzimidazol-6-one

7-ethoxycarbonyl-2-(1,3,4-thiadiazol-2-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-aminocarbonyl-2-(3,6-dimethylpyridazin-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-methylaminocarbonyl-2-(1,2,5-thiadiazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-dimethylaminocarbonyl-2-(2-oxopyran-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-cyano-2-(1,2,4-triazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-hydrazinocarbonyl-2-(3-pyrazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

7-acetyl-2-(2-imidazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 17,7-Dimethyl-2-(2-furanyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

(a) 6.5 g. (50 mmol) furan-2-carboxylic acid chloride are addeddropwise, with ice cooling, to a solution of 5.5 g. (25 mmol)6-amino-5-nitro-3,3-dimethylindolin-2-one in 50 ml. pyridine and thenstirred at 25° C. The crystalline slurry obtained is poured into about300 ml. water, filtered off with suction, washed with water and dried.The crude product is further used without purification. There areobtained 10.2 g.6-furanylcarbonylamino-5-nitro-3,3-dimethylindolin-2-one; m.p. 229°-235°C.

(b) 1.0 g. Palladium on charcoal (10%) are added to 10.0 g. (31.7 mmol)6-(2-furanylcarbonylamino)-5-nitro-3,3-dimethylindolin-2-one in 250 ml.ethanol. This suspension is hydrogenated at ambient temperature andnormal pressure. After completion of the take-up of hydrogen, thesolution is separated from the catalyst and evaporated to dryness. Thecrude product is further used without purification. There are obtained9.5 g. 6-furanoylamino-5-amino-3,3-dimethylindolin-2-one; m.p. 215°-224°C.

(c) 5.7 g. (20 mmol) 6-furanoylamino-5-amino-3,3-dimethylindolin-2-oneare heated for 1 hour at 80° C. in 200 ml. ethanol and 40 ml.concentrated hydrochloric acid. The solution is evaporated to dryness,rendered alkaline with 2N aqueous ammonia solution and extracted withmethylene chloride. The organic phase is evaporated and the residuepurified over silica gel (elution agent: methylenechloride/ammonia-saturated methanol 20:1 v/v). There is obtained 1.8 g.(33.3% of theory) of the desired product; m.p. 311°-316° C. afterrecrystallisation from ethyl acetate.

EXAMPLE 27,7-Dimethyl-2-(2-thienyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

A solution of 3.8 g. (20 mmol) 5,6-diamino-3,3-dimethylindolin-2-one,2.25 g. (20 mmol) thiophene-2-aldehyde and 4 ml. glacial acetic acid in40 ml. ethanol is heated under reflux for 1 hour and then further boiledfor 1 hour, while passing through air. The reaction mixture is thendistilled to dryness and the residue stirred up with ethyl acetate andfiltered off with suction. The crystallisate obtained is recrystallisedfrom acetone. Yield: 1.7 g. (30% of theory); m.p. 332°-336° C.

EXAMPLE 37,7-Dimethyl-2-(2-pyrrolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 2, from 3.8 g. (20 mmol)5,6-diamino-3,3-dimethylindolin-2-one, 1.9 g. (20 mmol)pyrrole-2-aldehyde and 0.4 g. (2 mmol) p-toluenesulphonic acid, afteracidification and evaporation of the reaction mixture, there is obtainedthe crude product of the title compound. For purification, the residueis worked up with water and the filtrate is neutralised with 2N aqueousammonia solution and filtered off with suction. The residue isrecrystallised from isopropanol with the addition of ethanolichydrochloric acid. The yield is 1.2 g. (20% of theory); m.p. of thehydrochloride >300° C.

EXAMPLE 47,7-Dimethyl-2-(2-pyrazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

(a) 5.1 g. (26 mmol) 5,6-diamino-3,3-dimethylindolin-2-one are dissolvedin 100 ml. methylene chloride and mixed with 5.5 g. (39 mmol)pyrazine-2-carboxylic acid chloride and 3.9 g. (39 mmol) triethylamine.After 1 hour at 25° C., the solvent is distilled off and the residue isworked up with water and filtered off with suction. The residue of mono-and diamide is recrystallised from ethyl acetate/methanol. Yield: 5.6g.; m.p. 269°-272° C.

(b) 5.6 g. of the mono- and diamide are stirred for 18 hours at 90° C.with 85 ml. ethanol and 85 ml. concentrated hydrochloric acid.Subsequently, the reaction mixture is evaporated, neutralised with 2Naqueous ammonia solution and filtered off with suction. The residue ispurified over silica gel (elution agent: methylene chloride/methanol19:1 v/v) and recrystallised from ethyl acetate/methanol. Yield: 0.85 g.(16% of theory); m.p. >300° C.

EXAMPLE 57,7-Dimethyl-2-(4-thiazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 4, starting from 3.8 g. (20 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 4.4 g. (30 mmol)thiazole-4-carboxylic acid chloride, there is obtained the titlecompound. Yield: 1.9 g. (33% of theory); m.p. 280° C., aftercrystallisation from methanol.

EXAMPLE 67,7-Dimethyl-2-(4-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

(a) 5.4 g. (40 mmol) 1-hydroxy-1H-benzotriazole are placed, togetherwith 5 g. calcium sulphate and 4.3 g. (35 mmol) pyridazine-4-carboxylicacid, in anhydrous dimethylformamide. 8.3 g. (40 mmol) N,N-dicyclohexylcarbodiimide in a little dimethylformamide are added dropwise thereto at0° C. After complete formation of the activated ester, 5.7 g. (30 mmol)5,6-diamino-3,3-dimethylindolin-2-one are added thereto and the reactionmixture is then stirred for 30 minutes. The dimethylformamide isdistilled off in a high vacuum, the residue is worked up with water andthe crude product of monoamide and dicyclohexylurea is filtered off withsuction and further used without purification. Yield: 20 g.

(b) The residue obtained according to (a) is mixed with 200 ml. ethanoland 40 ml. concentrated hydrochloric acid and heated under reflux for 2hours. After cooling, the dicyclohexylurea is filtered off with suctionand the ethanolic solution evaporated in a vacuum. The residue issuspended in water, rendered alkaline with 2N aqueous ammonia solutionand the title compound is filtered off with suction and recrystallised,with cooling, from ethyl acetate. Yield: 1.0 g. (12% of theory);m.p. >360° C.

EXAMPLE 77-Methyl-2-(4-pyridazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 6, starting from 6.0 g. (24 mmol)5,6-diamino-3-methylindolin-2-one dihydrochloride and 3.6 g. (28.8 mmol)pyridazine-4-carboxylic acid, there is obtained the title compound.Purification takes place by column chromatography on silica gel (elutionagent: methylene chloride/methanol 9:1 v/v). Yield: 0.15 g. (2.4% oftheory); m.p. >340° C.

EXAMPLE 87,7-Dimethyl-2-(5-pyrimidinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 6, from 0.164 g. (1.32 mmol)pyrimidine-5-carboxylic acid and 0.191 g. (1 mmol)5,6-diamino-3,3-dimethylindolin-2-one is obtained, after cyclisation ofthe crude product with glacial acetic acid, the title compound. Yield:70 mg. (25% of theory); m.p. 310°-312° C. after recrystallisation fromdioxan.

EXAMPLE 97,7-Dimethyl-2-(4-pyrimidinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 2, from 60 mg. (0.55 mmol) pyrimidine-4-aldehydeand 0.103 g. (0.54 mmol) 5,6-diamino-3,3-dimethylindolin-2-one, aftercolumn chromatography on silica gel (elution agent: methylenechloride/methanol 9:1 v/v), there is obtained the title compound. Yield:10 mg. (6.6% of theory); m.p. >300° C.

EXAMPLE 107,7-Dimethyl-2-(2-methylpyrimidin-5-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 6, starting from 5.7 g. (30 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 4.8 g. (35 mmol)2-methylpyrimidine-5-carboxylic acid, there is obtained the monoamide.Yield: 3.6 g. (39% of theory); m.p. 166°-170° C. after recrystallisationfrom water.

The crude product is subsequently cyclised with glacial acetic acid togive the title compound. Yield: 2.3 g. (68.5% of theory); m.p. >350° C.

EXAMPLE 117,7-Dimethyl-2-(4-imidazolyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 4, starting from 2.7 g. (14.1 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 2.8 g. (21.5 mmol)imidazole-4-carboxylic acid chloride, there is obtained the titlecompound. Yield: 0.17 g. (4.5% of theory); m.p. 270° C., afterrecrystallisation from methanol.

EXAMPLE 127,7-Dimethyl-2-(6-hydroxypyridazin-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 8, starting from 4.9 g. (35 mmol)6-hydroxypyridazine-3-carboxylic acid and 5.7 g. (30 mmol)5,6-diamino-3,3-dimethylindolin-2-one, there is obtained the titlecompound. Yield: 2.8 g. (32% of theory); m.p. >350° C., recrystallisedfrom ethanol.

EXAMPLE 137,7-Dimethyl-2-(1,2,4-1H-triazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 2, starting from 0.38 g. (2 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 0.195 g. (2 mmol)1,2,4-triazole-3-aldehyde, there is obtained the title compound. Yield:0.15 g. (28% of theory); m.p. >350° C.

EXAMPLE 147,7-Dimethyl-2-(2-methyloxazol-4-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 10, starting from 764 mg. (4 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 672 mg. (5.32 mmol)2-methyloxazole-4-carboxylic acid, there is obtained the title compoundafter purification on silica gel (elution agent: methylenechloride/methanol 8:2 v/v). Yield: 0.3 g. (26.6% of theory); m.p.315°-318° C.

EXAMPLE 157,7-Dimethyl-2-(5-methylpyrazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

Analogously to Example 2, starting from 0.57 g. (3 mmol)5,6-diamino-3,3-dimethylindolin-2-one and 0.33 g. (3 mmol)5-methylpyrazole-3-aldehyde, there is obtained the crude product afterrendering the reaction mixture alkaline with concentrated aqueousammonia solution. The residue is purified over silica gel (elutionagent: methylene chloride/ammonia-saturated methanol 10:3 v/v). Yield:0.22 g. (26% of theory); m.p. 245°-250° C., crystallised from water.

EXAMPLE 167-Methyl-7-ethoxycarbonyl-2-(2-pyrazinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

(a) 5.0 g. (18.5 mmol) 3-methyl-3-ethoxycarbonyl-6-aminoindolin-2-onehydrochloride are suspended in 60 ml. methylene chloride and mixed with12.5 ml. (90.4 mmol) triethylamine. 6.4 g. (45.2 mmol)pyrazine-2-carboxylic acid chloride are then added portionwise, whilecooling with ice, and the reaction mixture is further stirred for 3hours. The reaction mixture is evaporated, worked up with water,filtered off with suction and purified by column chromatography (elutionagent: methylene chloride/methanol 99:1 v/v). There are obtained 4.0 g.(65% of theory)3-methyl-3-ethoxycarbonyl-6-(2-pyrazinoylamino)-indolin-2-one, m.p.213°-214° C., (recryst. from ethanol).

(b) 3.4 g. (10 mmol)3-methyl-3-ethoxycarbonyl-6-(2-pyrazinoylamino)-indolin-2-one aredissolved in 20 ml. concentrated sulphuric acid and mixed dropwise at 0°to 5° C. with a solution of 1.1 g. (11 mmol) potassium nitrite inconcentrated sulphuric acid. After 3 hours, the reaction mixture ispoured on to ice, filtered off with suction and the residue is suspendedin water, neutralised with aqueous ammonia solution, filtered off withsuction and recrystallised from ethanol. There are obtained 3.2 g. (83%of theory)3-methyl-3-ethoxycarbonyl-5-nitro-6-(2-pyrazinoylamino)indolin-2-one;m.p. 237°-238° C.

(c) 3.2 g. (8.3 mmol)3-methyl-3-ethoxycarbonyl-5-nitro-6-(2-pyrazinoylamino)-indolin-2-one in100 ml. ethanol are hydrogenated in 100 ml. ethanol in the presence of0.5 g. 10% palladium on charcoal. After completion of the take up ofhydrogen, the solution is filtered off from the catalyst, the ethanol isevaporated off and the residue is stirred for 1 hour in glacial aceticacid at 60° C. The glacial acetic acid is evaporated, the residue istaken up in water, filtered and recrystallized from ethanol. There areobtained 1.8 g (65% of theory) of the title compound, m.p. 288°-290° C.

EXAMPLE 177,7-Dimethyl-2-(1,2,5-thiadiazol-3-yl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one

2.0 g. (15.3 mmol) 1,2,5-thiadiazole-3-carboxylic acid and 2.6 g. (13.6mmol) 5,6-diamino-3,3-dimethyl-indolin-2-one are heated in 40 ml.polyphosphoric acid under an atmosphere of nitrogen for 2 hours at 160°C. The warm solution is poured on to ice water, worked up and thecrystals obtained are filtered off with suction. The residue is againsuspended in water, neutralised with an aqueous solution of ammonia,filtered off with suction and recrystallised from methanol with theaddition of charcoal. Yield: 2.6 g. (66% of theory); m.p. >300° C.

Pharmaceutical Activity

The following experiment demonstrates the pharmaceutical activity ofcompound (I) of the invention:

Male Sprague-Dawley rats weighing between 350 and 450 g were narcotizedby intraperitoneal injection of a barbiturate and fitted withinstrumentation for the examinations as follows:

A pressure measuring catheter (Millar Mikrotip™/diameter 0.5 mm) wasinserted through the arteria carotis dextra into the left ventricle. Thepressure inside the left ventricle was continually registered throughthis catheter. The signal from this mikrotip was electronicallydifferentiated and (dp/dt)₆₀ --the slope of the pressure-time curve at apressure of 60 mm Hg--was taken as a measure for the inotropy.

A polypropylene catheter was bound in a vena jugularis for theintravenous injection of the test substances.

A further polypropylene catheter was inserted through an arteriafemoralis into the abdominal aorta for the direct measurement of thearterial blood pressure.

The ECG was traced with subcutaneous insertion electrodes.

During the preparation of the animal and during the entire test periodthe rats were fixed on a electrically heated and thermostated operatingtable.

The test substances were always introduced by intravenous injection,with an injection volume, per injection, of 1 ml/kg body weight. Inintervals of 10 min. each, doses increasing from 0.01 to 30 mg of thetest substances were intravenously injected. In this way dose effectcurves for the measured parameters for the investigated substances wereobtained.

From the measured data, using a regression calculation, equipotent dosesfor the positively inotropic effect Δ(dp/dt)₆₀ were calculated. Inaddition, as criteria for the effectiveness of the substances, themaximum effect obtained maximal increase of (dp/dt)₆ and itscorresponding dose were determined. Table (I) below shows the equipotentdoses (DE₁.5 =the dose in mg/kg that leads to an increase of (dp/dt)₆₀of 1.5 mHg/sec) and the maximal effectiveness (W_(max) =the maximalincrease of (dp/dt)₆₀.

                  TABLE (I)                                                       ______________________________________                                               DE.sub.1.5 mHg/sec                                                                       W.sub.max                                                   Substance                                                                              [mg/kg i.v.] [mHg/sec]  [mg/kg i.v.]                                 ______________________________________                                        Ex. 1    0.07         2.9        3.0                                          Ex. 2    0.12         2.1        0.3                                          Ex. 3    0.45         2.6        10.0                                         Ex. 4    0.10         2.6        10.0                                         Ex. 5    0.14         2.0        0.3                                          Ex. 6    0.04         2.4        0.3                                          Ex. 8    0.05         3.1        3.0                                          Ex. 13   0.1          3.1                                                     Ex. 16   0.12         2.6                                                     Ex. 17   0.007        3.5                                                     Ref. 1   1.17         3.5        10                                           Ref. 2   >>3.0        0.6        3.0                                          ______________________________________                                    

The corresponding dose is shown in brackets. The values show, that thesubstances of Example 6, 8 and 1 are more potent than the substances,used as standards (Ref. 1 and Ref. 2).

Ref. 1: 3-Amino-6-methyl-5-phenyl-2-(1H)-pyridinonemethane-sulfonate(from British Patent Application GB No. 2,070,606).

Ref. 2:3,4-Dihydro-6-[4-[3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone(from U.S. Pat. No. 4,415,572).

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

Described herein are indoline compounds of the general formulae (II) and(III) which are new and the subject of the present invention. Compoundsof the general formula (II) are obtained from compounds of the generalformula XIII, wherein R₁, R₂, and T have the same meanings as above, byreaction with compounds of general formula (IX). ##STR7## Compounds ofthe general formula (III) are obtained from compounds of the generalformula (XIV), wherein R₁, R₂, and T have the same meanings as above, byreaction with compounds of the general formula (IX). ##STR8## Thecompounds of general formulae (XIII) and (XIV) are known from theliterature (cf. Federal Republic of Germany Patent Application No. P 3417 643.8).

The reactions of the compounds of the general formulae (XIII) and (XIV)with carboxylic acid derivatives (compounds of general formula (IX)) togive amides of general formulae (II) and (III) take place in an inertsolvent, preferably in methylene chloride or pyridine at temperaturesbetween 0° C. and the boiling point of the solvent. The reaction canalso be carried out with carboxylic acids of the general formula IX,wherein Het andX have the same meanings as above and Y represents thehydroxy group. This reactions take place in a solvent or solventmixture, for example ethanol, isopropanol, benzene, toluene, in thepresence of a condensation agent, for example phosphorus oxychloride,thionyl chloride, or in polyphosphoric acid.

Apart from the compounds mentioned in the following examples, compoundsof general formulae (II) and (III) according to the present inventionalso include the following compounds:

5-(2-furanoylamino)-indolin-2-one

5-(2-thiophenoylamino)-3-i-propyl-indolin-2-one

5-[(5-methyl-pyrazol-3-yl)carbonylamino]-3,3-dimethyl-indolin-2-one

6-[(2-methyl-oxazol-4-yl)carbonylamino]-3,3-dimethyl-indolin-2-one

6-[(1.2.4-triazol-3-yl)carbonylamino]-3,3-dimethyl-indolin-2-one

6-[(1.2.5-thiaziazol-3-yl)carbonylamino]-3,3-dimethyl-indolin-2-one

6-[(6-hydroxy-pyridazin-3-yl)carbonylamino]-3-methyl-3-ethoxycarbonyl-indolin-2-one

6-[(2-hydroxypyrimidin-5-yl)carbonylamino]-3-methyl-3-aminocarbonylindolin-2-one

as well as those indolines leading to the compounds of examples 1-16 andthe general compounds as described above for pyrrolobenzimidazoles.Therefore the following examples and the above eight examples areillustrative of the compounds of the invention and should not limit theinvention only to the compounds of the examples.

EXAMPLE 18

Analogously to example 16a, 6-amino-3,3-dimethyl-indolin-2-one isreacted with the following acid chlorides to yield the following amides:

    __________________________________________________________________________                           melting                                                                           recrystallization                                  compound            yield                                                                            point                                                                             solvent                                            __________________________________________________________________________    a 3,3-dimethyl-6-(2-furanoylamino)-                                                               54%                                                                              271-                                                                              CH.sub.3 OH/DMSO                                     indolin-2-one        274° C.                                           from furan-2-carbonylchloride                                               b 3,3-dimethyl-6-(2-thiophenoylamino)-                                                            40%                                                                              268-                                                                              CH.sub.3 OH/DMSO                                     indolin-2-one        271° C.                                           from thiophen-2-carbonyl chloride                                           c 3,3-dimethyl-6-(4-imidazolyl-carbonyl-                                        amino)-indolin-2-one                                                          from imidazol-4-carbonyl chloride                                           d 3,3-dimethyl-6-(1,2,3-thiadiazol-4-yl-                                                          36%                                                                              255-                                                                              CH.sub.3 OH/DMSO                                     carbonylamino)indolin-2-one                                                                        258° C.                                           from 1,2,3-thiadiazol-4-                                                      carbonyl chloride                                                           e 3,3-dimethyl-6-(2-thiophenyl-ethanoyl-                                                          17%                                                                              222-                                                                              column                                               amino)indolin-2-one  225° C.                                                                    chromatography:                                      from thiophen acetic acid chloride                                                                     CH.sub.2 Cl.sub.2 :CH.sub.3 OH =                                              9:0.2                                              f 3,3-dimethyl-6-[3-(5-methyl-pyrazol-                                          3-yl)propenoylamino]-indolin-2-one                                            from 3-(5-methylpyrazol-3-yl)-                                                propenoic acid chloride                                                     __________________________________________________________________________

EXAMPLE 19

Analogously to example 16a,6'-amino-spiro[cyclopentane-1,3'-indolin]-2'-one is reacted with thefollowing acid chlorides to yield the following amides:

    ______________________________________                                                                             re-                                                                           crystal-                                                              melting lized                                    Compound              yield  point   from                                     ______________________________________                                        a   6'-(2-furanoylamino)-spiro-                                                                         68%    254-  ethanol                                    [cyclopentan-1,3'-indolin]-2'-one                                                                          255° C.                                   from furan-2-carbonylchloride                                             b   6'-(2-thiophenoylamino)-spiro-                                                                      71%    272-  ethanol                                    [cyclopentan-1,3'-indolin]-2'-one                                             from thiopen-2-carbonylchloride                                           c   6'-[3-(5-methylpyrazol-3-yl)propenoyl-                                        amino]spiro[cyclopentan-1,3'-indolin]-                                        2'-one                                                                        from 3-(5-methylpyrazol-3-yl)-                                                propenoic acid chloride                                                   ______________________________________                                    

EXAMPLE 20

Analogously to example 16a, 5-amino-3,3-dimethyl-indolin-2-one isreacted with the following acid chlorides to yield the following amides,

    ______________________________________                                                                            re-                                                                           crystal-                                                              melting lized                                     compound             yield  point   from                                      ______________________________________                                        a   3,3-dimethyl-5-(2-furanoylamino)-                                                                  15%    223-  ethyl                                       indolin-2-one               225° C.                                                                      acetate                                     from furan-2-carbonyl chloride                                            b   3,3-dimethyl-5-(2-thiophenoyl-                                                                     59%    245-  ethyl                                       amino)indolin-2-one         246° C.                                                                      acetate                                     from thiophen-2-carbonyl chloride                                         ______________________________________                                    

What is claimed:
 1. An indoline or tautomer thereof, of the formula: ##STR9## wherein R₁ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₃ -C₇ cycloalkyl;R₂ is hydrogen, cyano, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, or a carbonyl group substituted by hydroxyl, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, amino, C₁ -C₆ alkylamino, C₂ -C₁₂ dialkylamino or hydrazino, or R₂ and R₁ together with the carbon to which they are attached from a C₃ -C₈ spirocycloalkyl ring, or R₁ and R₂ together from C₃ -C₇ alkylidene or C₃ -C₇ cycloalkylidene, X is a valency bond, C₁ -C₄ alkylene or vinylene and T is oxygen or sulphur; and Het is furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyronyl, pyridazinyl, N-N-dioxypyrazinyl, N-N-dioxypyrimidinyl, oxazinyl, thiazinyl, triazinyl or tetrazinyl wherein the heterocyclic five- and six-membered rings are unsubstituted or substituted by one or more C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, hydroxyl, oxo, nitro, amino, halo, carboxyl, C₂ -C₇ alkoxycarbonyl, aminocarbonyl or cyano groups.
 2. The indoline compound of claim 1, wherein R₁ is hydrogen, methyl, ethyl, cyclopentyl or cyclohexyl, and R₂ is hydrogen, methyl, ethyl, isopropyl, allyl, cyano, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl or hydrazinocarbonyl or R₁ or R₂, together with the carbon atom to which they are attached, represent a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl ring or R₁ or R₂ together represent isopropylidene, X is a valency bond, or methylene or vinylene, T is oxygen and Het is a pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl group, and wherein the heterocyclic five- or six-membered rings can be substituted one or more times by oxo, hydroxyl, methyl, methoxy, methylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, amino, nitro, halo or cyano.
 3. The indoline compound of claim 1 wherein R₁ is hydrogen, methyl or ethyl, R₂ is methyl, ethyl, isopropyl, aminocarbonyl or ethoxycarbonyl or R₁ and R₂, together with the carbon atom to which they are attached, form a spirocyclopentane ring, X is a valency bond or vinylene or methylene, T is oxygen and Het is furanyl, thiophenyl, imidazolyl, triazolyl, oxazolyl, pyrazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein the heterocyclic rings are unsubstituted or are substituted one or more times by hydroxyl, methyl or carboxyl.
 4. The indoline compound of claim 1, wherein R₁ is hydrogen or methyl and R₂ is hydrogen, methyl or ethoxycarbonyl, or R₁ and R₂ together with the carbon atom to which they are attached form a spirocyclopentane, X is a valency bond methylene or vinylene, T is oxygen and Het is a furanyl, pyrrolyl, pyrazinyl, thiazolyl, thiadiazolyl, pyridazinyl or pyrimidinyl.
 5. The indoline compound of claim 1 wherein R₁ and R₂ are the same and are methyl or hydrogen.
 6. The indoline compound of claim 1 wherein R₁ and R₂ form a C₃ -C₈ spirocycloalkyl ring.
 7. The indoline compound of claim 1 wherein R₁ and R₂ form a spirocyclopentyl ring.
 8. The indoline compound of claim 1 wherein Het is a furanyl, thiophenyl, pyrazolyl, triazolyl, oxazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, imidazolyl or pyrimidinyl ring, wherein the heterocyclic rings are unsubstituted or are substituted one or more times by hydroxyl or methyl.
 9. The indoline compound of claim 1 wherein Het is a furanyl, thiophenyl, pyrazolyl, thiadiazolyl, pyrazinyl or imidazolyl ring, wherein the heterocyclic rings are unsubstituted or are substituted by hydroxyl or methyl.
 10. The indoline compound of claim 1 designated 3,3-dimethyl-6-(2-furanoylamino)-indoline-2-one.
 11. The indoline compound of claim 1 designated 3,3-dimethyl-6-(2-thiophenoylamino)-indoline-2-one.
 12. The indoline compound of claim designated 3,3-dimethyl-6-(1,2,3-thiadiazol-4-yl-carbonylamino)indoline-2-one.
 13. The indoline compound of claim 1 designated 3,3-dimethyl-6-(2-thiophenyl-ethanoyl-amino)indoline-2-one. 